Carcinogenesis Advance Access originally published online on November 13, 2007
Carcinogenesis 2008 29(2):252-262; doi:10.1093/carcin/bgm249
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Loss of type III transforming growth factor β receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression
1 Department of Pharmacology and Cancer Biology
2 Department of Medicine
3 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
* To whom correspondence should be addressed. Tel: +1 919 668 1352; Fax: +1 919 668 2458; Email: blobe001{at}mc.duke.edu
Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor β (TGF-β) signaling pathway is a key regulator of EMT. The TGF-β superfamily coreceptor, the type III TGF-β receptor (TβRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TβRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-β type I and type II receptors are maintained at the mRNA level. Loss of TβRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TβRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TβRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TβRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TβRIII, generating soluble TβRIII (sTβRIII). In human pancreatic cancer specimens, TβRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TβRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTβRIII in suppressing EMT-associated increases in motility and invasion.
Abbreviations: CM, conditioned media; EMT, epithelial to mesenchymal transition; NTC, non-targeting control; sTβRIII, soluble TβRIII; TGF-β, transforming growth factor β
Received July 30, 2007; revised October 30, 2007; accepted November 3, 2007.